Stereoselective Construction of 3-(Aminoalkylidene)oxindoles in One Pot: Development of a Novel, Robust, and Scalable Process for the Multigram-Scale Preparation of Nintedanib

A palladium-catalyzed novel stereoselective Heck/Buchwald–Hartwig cascade reaction of substituted N-(2-iodophenyl)propiolamides and amines has been established to furnish a series of 3-(aminoalkylidene)oxindole scaffolds with good yields. In addition, we report the development of a robust, scalable, and convergence approach leading to the synthesis of nintedanib (1). Salient features of the approach include the production of key oxindole intermediate 17 via our advanced Heck/Buchwald–Hartwig reaction cascade, which enables the reduction of the number of synthetic steps. Moreover, our approach avoids the expensive column chromatography purification method for all synthetic steps. Further, we also disclosed an alternative route toward the synthesis of another kinase inhibitor hesperadin (2) following the above-mentioned cascade method.